Narcotic use in chronic pain treatment has played a major role in the ongoing opioid crisis. Convergent evidence indicates that the activity of the anterior cingulate cortex (ACC) is critical in the pathophysiology of chronic pain. Local therapies directed to the ACC yield benefit for chronic pain clinically and preclinical data suggest that locally applying the drug ketamine to the ACC should yield acute-onset and long-acting remission of the pain phenotype through a non-opioid mechanism. In this manner, local ketamine infusion into this critical brain target is a promising non-opioid pain treatment that could yield remission of chronic pain with potentially more predictable dose-response relationships than systemic administration, with personalization based on the imaging defined sensitivity of the ACC to pain, and without limiting side effects due to off-target drug action in the rest of the brain or body. To translate these results into a clinical treatment, one would ideally be able to locally apply ketamine to only the ACC, without any off-target ketamine action and without invasive interventions to the brain. Towards this end, we have developed ultrasonic drug uncaging for neuroscience, in which neuromodulatory agents are uncaged from ultrasound-sensitive biocompatible and biodegradable drug-loaded nanocarriers. We have validated that we can use this technique for selective ultrasound-induced release of ketamine, and that ultrasonic uncaging yields drug effects that are limited precisely by when and where the ultrasound is applied. Further, we have developed a straightforward path to translate this technology to clinical practice. We now propose to clinically translate ultrasonic ketamine uncaging for chronic pain therapy. Given the variety of potential therapeutic effects that are increasingly ascribed to ketamine, we anticipate that this first-in-human clinical trial would establish the safety of this technique and generate the efficacy data necessary to enable regulatory approval for larger clinical trials for each application of ultrasonic ketamine uncaging. Overall, we expect that completion of this proposal will provide the prototype for subsequent translation of ultrasonic drug uncaging for numerous other drugs of interest. Specifically, in the proposed preclinical UG3 phase, we will scale up our nanoparticle production processes to human scales and adapt them to pharmaceutical standards. We will also complete the animal testing needed to obtain regulatory approval for an initial clinical trial. In the proposed clinical UH3 phase, we will complete a first- in-human evaluation of the safety and efficacy of ultrasonic ketamine uncaging by quantifying how much ketamine is released relative to the ultrasound dose, and assessing whether the uncaged ketamine can modulate the sensitivity and affective response to pain, in patients suffering from chronic osteoarthritic pain. Successful completion of this proposal will yield a novel, noninvasive, and non-opioid therapy for chronic pain that maximizes the therapeutic efficacy of ketamine over its side effects, by targeting its action to a critical hub of pain processing.